Abnormally high levels of circulating lipids (hyperlipidemias) are a major predisposing factor in development of atherosclerosis. Elevated levels of serum cholesterol and cholesteryl esters, which are carried by the beta-lipoprotein or low density lipoprotein (LDL) and lipoprotein (a) (Lp(a)) fractions of serum lipids, are known to be atherogenic. Also implicated in cardiovascular disease are elevated levels of triglycerides, carried mostly in the very low density lipoprotein (VLDL) fraction.
Drugs which lower serum lipids (i.e., hypolipemic drugs) frequently are prescribed to retard development of atherosclerotic lesions in individuals exhibiting hyperlipidemias. Many of these drugs are effective when taken regularly, but suffer from poor patient compliance due to unpleasant side effects. Examples of effective but underutilized hypolipemic drugs include the bile acid-binding resins, such as cholestyramine.
The ability of large doses of nicotinic acid (i.e., niacin) to lower serum lipid levels has been recognized for many years. This drug is unusually effective because it lowers the levels of several classes of morbidity-associated serum lipids, including LDL cholesterol (LDL-C), Lp(a), and triglycerides (Tg). In addition to its antilipemic activity, niacin is also an essential water-soluble vitamin. Nicotinic acid exhibits relatively low toxicity on a molar basis.
However, the doses required to lower atherogenic serum lipids are quite large, on the order of 1-8 grams per day. At these levels, adverse side effects are frequent, and may include gastrointestinal disturbances such as nausea, heartburn, and diarrhea. However, the most frequent and prominent side effect is intense flushing, often accompanied by cutaneous itching, tingling, or warmth, and occasionally by headache. Although the flushing side effect is in general harmless, it is sufficiently unpleasant that patient compliance is markedly reduced. Often, 30-40% of patients cease taking nicotinic acid within days after initiating therapy. Consequently, significant efforts have been exerted to develop niacin analogs, dosage forms, and treatment protocols which minimize the flush reaction.
Tolerance to the flush reaction develops after a few days or weeks of repeated administration of nicotinic acid. One strategy for administration is to begin with low doses, i.e., 125 mg twice daily, then to increase the daily dose by increments of 30-100% after 1-6 weeks at each dose level; see, e.g., McKenney et al., J. Am. Med. Assn. 271:672-710 (1994). This procedure reduces but does not eliminate the flush reaction. Ibid. A further difficulty with relying upon tolerance for suppression of the flush reaction is that tolerance is lost rapidly if the drug is discontinued for a day or two. Consequently, the dose must be reduced again when administration is resumed.
Another method of reducing flush is to administer a sustained release (SR) form of nicotinic acid. Sustained release preparations reportedly have a lower incidence of flushing and gastrointestinal side effects, and concomitantly greater patient compliance and tolerance; see King et al., Am. J. Med. 97:323-331, 329 (1994); Knopp et al., Metabolism 34:642-650 (1985); Alderman et al., Am. J. Cardiol. 64:725-729 (1989).
However, even sustained release preparations are not tolerated by a significant fraction of the patient population; see Luria et al., Arch. Into Med. 148:2493-2495 (1988). Moreover, sustained release dosage forms are prone to induce a much more severe side effect, hepatic toxicity; see, e.g., Rader et al., Am. J. Med. 92:77-81 (1992).
Recent studies have indicated that the flushing reaction is initiated by release of prostaglandin D. Prostaglandins are known to cause vasodilation, as well as a subjective experience of discomfort. Evidence supporting the role of prostaglandin D in mediating the niacin-induced flush includes the observation that a dramatic rise in the concentration of prostaglandin F2, a metabolite of D, occurs in the blood coming from the skin following administration of niacin. Furthermore, the level of prostaglandin F2 decreases markedly after 6 days of continuous, twice daily administration of nicotinic acid. This decrease in nicotinic acid-induced prostaglandin F2 correlates with the development of tolerance to the flush reaction which usually develops upon prolonged administration. Therefore, tolerance appears to reflect a decline in prostaglandin D release, rather than an increase in metabolic inactivation of nicotinic acid.
Several nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the synthesis of one or more prostaglandins (PGs) by blocking the enzyme prostaglandin synthetase, also referred to as cyclooxygenase. Among the NSAIDs in clinical use are aspirin, ibuprofen, naproxen, phenylbutazone, indomethacin, and flufenamic acid and its congeners. These NSAIDs inhibit the synthesis of PGs such as E2 and F2, but typically at high micromolar (.mu.M) concentrations; see, e.g., Flower, Pharmacol. Rev. 26:33 (1974) (see Table 1 therein).
The prostaglandin synthetase inhibitors aspirin and indomethacin have been shown to reduce the cutaneous flush induced by nicotinic acid. Anderson et al., Acta Pharmacol. Toxicol. 41:1-10 (1977), demonstrated that nicotinic acid-induced flush in guinea pigs, as measured by an increase in ear temperature, was inhibited by pretreatment at 4.5 and 0.5 hr with indomethacin (25 or 50 mg/kg) or aspirin (50,100, or 200 mg/kg). An aspirin total dose of 975 mg, administered to human subjects in a divided dose of 650 mg at 1 hr and 325 mg at 0.5 hr prior to high dose nicotinic acid challenge, was shown to significantly reduce cutaneous flush; see Wilken et al. Clin. Pharmacol. Ther. 31:478-482 (1982).
A nicotinic acid ester derivative, methyl nicotinate, which causes local cutaneous erythema when administered topically, was used to study the flush-inhibiting effects of aspirin.
The effect of aspirin on niacin-induced cutaneous reactions has been studied clinically; see Whelan et al. J. Fam. Pract. 34:165-168 (1992). The authors of this study concluded that 325 mg of aspirin will decrease the warmth and flushing associated with niacin, but not the itching and tingling. In this study, either aspirin or a placebo was administered 30 minutes prior to niacin. As compared to the control group (to whom a placebo was administered prior to niacin), an 80 mg dose of aspirin appeared to have caused even more aggravated flushing, warmth, itching and tingling than pre-administration of the placebo. However, even a 325 mg dose of aspirin administered 30 minutes prior to niacin resulted in flushing and warmth in at least 72% of the patients.
NSAIDs such as aspirin inhibit cyclooxygenase and are therefore considered prostaglandin synthetase inhibitors. Thus, aspirin is considered to be the best NSAID for prevention of platelet aggregation (thrombosis) because it is a long-lasting inhibitor of platelet cyclooxygenase, and it irreversibly acetylates the enzyme. Platelet cyclooxygenase cannot by restored by protein biosynthesis because platelets lack a nucleus.
With regard to inhibiting platelet aggregation, the ex vivo effect of aspirin has been studied in patients taking aspirin for recurrent ischemic stroke prevention; see Helgason et al. Stroke 25:2331-2336 (1994). In this study, increasing doses of aspirin were administered to patients with previous ischemic stroke, and the extent of platelet aggregation inhibition was determined periodically. Over 33 months of initial testing, 288 out of 306 patients had complete inhibition, and 78 out of 306 had partial inhibition. However, at repeat testing, about 33% of the patients having complete inhibition at initial testing had lost part of the anti-platelet effect of aspirin and had converted from complete to partial inhibition without a change in aspirin dosage. Of 52 patients with partial inhibition at initial testing, 35 achieved complete inhibition either by dosage escalation or fluctuation of response at the same dosage, but 8 of the 35 reverted to partial inhibition on further testing. Thus, the anti-platelet (and presumably antithrombotic) effect of a fixed dose of aspirin was not constant over time in all individuals. Furthermore, the mechanisms by which the increased dosage requirement of aspirin resistance develop, and the clinical significance of this development, remained undefined.
Further, a method for reducing platelet aggregation in which patients having a predisposition for thrombus formation are treated with compositions of aspirin, citric acid, thiamine and/or a zinc salt is known (see U.S. Pat. No. 5,401,730; incorporated herein by reference in its entirety). The combination of aspirin and citric acid is believed to be more effective than aspirin alone. Further, thiamine is believed to contribute to the reduction in thrombotic potential by reducing plasma fibrinogen levels.